While the success of cancer treatment depends greatly on early detection, many types of cancers remain undiagnosed in early stages of the disease. Breast cancer is the second leading cause of cancer-related deaths of women in North America. Prostate cancer is the most common noncutaneous malignant disease among males. The incidence of prostate cancer increases more rapidly with age than any other type of cancer, and it often causes death while remaining undiagnosed. Bladder cancer is potentially curable if treated in the early stages of tumor development, but recurrence rates are high. Ovarian cancer is the most common cause of gynecological cancer death, with most patients diagnosed during the advanced stages of the disease. Lung cancer is the most common cause of cancer deaths, second behind prostate cancer in occurrence for males and third behind breast and colorectal cancers for women.
One area of advancement in early detection of cancers has centered on the identification of mutations in tumor suppressor genes. Tumor suppressor genes have been shown to regulate the development of many types of cancer. For example, abnormal expression of mutated p53 tumor suppressor gene has been demonstrated in breast, prostate, and ovarian carcinoma cell lines and/or tumor samples. Rubin, et al., “Two prostate carcinoma cell lines demonstrate abnormalities in tumor suppressor genes,” J Surg Oncol 46:1–6 (1991); Munshi, et al., “p53 molecule as a prognostic marker in human malignancies,” J La State Med Soc 150:175–178 (1998); Suzuki, et al., “Loss of heterozygosity on chromosome 6q27 and p53 mutations in epithelial ovarian cancer,” Med Oncol 15:119–123 (1998). Germline mutations in both BRCA1 and BRCA2 genes have been found in breast and ovarian cancer patients. Randall, et al., “Germline mutations of the BRCA1 and BRCA2 genes in a breast and ovarian cancer patient,” Gynecol Oncol 70:432–434 (1998).
The antiproliferative human prohibitin gene, which maps to chromosome 17 at q21 (White, et al., “Assignment of the human prohibitin gene (PHB) to chromosome 17 and identification of a DNA polymorphism,” Genomics 11:228–230 (1991)) has been examined in association with various types of cancer. In one study, a large number of human tumors of the breast, ovary, liver, and lung were examined for somatic mutations in the prohibitin gene, and although mutations were observed in a few sporadic breast cancers, none were identified in any of the other cancers. Sato, et al., “The human prohibitin (PHB) gene family and its somatic mutations in human tumors,” Genomics 17:762–764 (1993). Cliby, et al. also demonstrated that the prohibitin gene does not play a role in ovarian carcinogenesis. Cliby, et al., “Absence of prohibitin gene mutations in human epithelial ovarian tumors,” Gynecol Oncol 50:34–37 (1993). Asamoto and Cohen demonstrated that prohibitin overexpression but not mutation was involved in the early stages of rat bladder carcinogenesis. Asamoto, M. and Cohen, S. M., “Prohibitin gene is overexpressed but not mutated in rat bladder carcinomas and cell lines,” Cancer Lett 83:201–207 (1994). While prohibitin was an initial candidate gene for a familial breast and ovarian tumor suppressor locus based on a frequent loss of heterozygosity in this region in familial and sporadic breast cancers (Sato, et al., “The human prohibitin gene located on chromosome 17q21 in sporadic breast cancer,” Cancer Res 52:1634–1646 (1992)), positional cloning studies resulted in the identification of BRCA1 rather than prohibitin as a familial breast cancer gene on chromosome 17 (Miki, et al., “A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1,” Science 266:66–71 (1994)). Additional studies did not identify any somatic mutations in the prohibitin protein coding region in familial/hereditary breast cancers suggesting that the protein coding region is not frequently mutated in breast cancers. Sato et al., Genomics 17:762–764 (1993).
In WO 96/40919, Dell'Orco et al. identified mutations in the 3′ untranslated region (3′UTR) of the prohibitin gene (SEQ ID NO:1) which are diagnostic for increased susceptibility to cancer, particularly breast cancer. Full length prohibitin cDNAs for the BT-20, MCF7 and SK-BR-3 breast cancer cell lines were sequenced, and mutations restricted to the 3′ UTR were identified. These three cell lines were also arrested in cell cycle progression when full length prohibitin transcript was introduced by microinjection. All of them were also homozygous for the B-allele. Compared to the sequence of the wild type prohibitin 3′ UTR (WT) (SEQ ID NO:1), two point mutations were identified for BT-20: G (guanine) to A (adenine) at position 758 and T (thymine) to C (cytosine) at position 814. MCF7 also had two point mutations: G to A at position 236 and C to T at position 729. SK-BR-3 showed 26 base changes including a change of C to T at position 729. Thus, MCF7 and SK-BR-3 both had a change of C to T at position 729.
In WO 98/20167, Jupe et al. disclosed that, contrary to the teachings of the prior prohibitin work, this change from C to T at position 729 is the result not of a somatic mutation, but rather the result of a natural allelic variation at this point, i.e., it is a germline polymorphism. Furthermore, it is a germline polymorphism that can be used as a susceptibility marker for breast cancer. Carriers of the T-allele (C/T) have an approximately 2-fold increased risk of developing breast cancer. Further, data indicate that the frequency of homozygosity for 729-T appears to be approximately 4–5-fold higher in breast cancer patients than in unaffected females, that 4% of all breast cancers develop in women who are homozygous T/T (which likely make up less than 1% of unaffected women), and that their lifetime risk of developing breast cancer is approximately 50%.
It has now been found that the prohibitin gene, located on chromosome 17q21 near the BRCA1 locus, exhibits a germline polymorphism in the 3′UTR that can be used as a susceptibility marker for other types of cancer.